ABSTRACT
The incidence of human papilloma virus-mediated oropharyngeal squamous cell carcinoma (OPSCC) has increased over the past 40 years, particularly among young individuals with a favorable prognosis; however, current therapy often leads to unfortunate side effects, such as dysphagia. Despite the emphasis on dysphagia in previous studies, there is an important research gap in understanding the correlation between neuronal changes and patient-reported and functional outcomes in patients with OPSCC. To address this issue, we examined pathologic tissue samples from patients with OPSCC using multiplex immunofluorescence staining and machine learning to correlate tumor-associated neuronal changes with prospectively collected patient-reported and functional outcomes. We found that tumor enrichment of adrenergic (TH+) and CGRP+ sensory-afferent nerves correlated with poorer swallowing outcomes. Functional electromyography recordings showed correlations between growing (GAP43+) and immature cholinergic (ChAT+DCX+) nerves and denervation patterns in survivors of OPSCC. A murine model of radiation-induced dysphagia further confirmed that immature cholinergic and CGRP+ nerves were correlated with impaired swallowing. Preclinical interventional studies also supported the independent contributions of CGRP+ and cholinergic (ChAT+) nerves to dysphagia in treated mouse models of OPSCC. Our results suggest that CGRP+ and ChAT+ neuronal signaling play distinct roles in tumor- and radiation-induced dysphagia in OPSCC and offer a comprehensive dataset on the neural landscape of OPSCC. These insights may guide early interventions for swallow preservation and the repurposing of neurology-related drugs, such as CGRP blockers, in clinical oncology and survivorship.
Subject(s)
Carcinoma, Squamous Cell , Deglutition Disorders , Oropharyngeal Neoplasms , Humans , Oropharyngeal Neoplasms/radiotherapy , Oropharyngeal Neoplasms/pathology , Animals , Carcinoma, Squamous Cell/radiotherapy , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/physiopathology , Male , Mice , Deglutition/radiation effects , Female , Middle Aged , Treatment Outcome , Calcitonin Gene-Related Peptide/metabolismABSTRACT
BACKGROUND: Nelarabine is a purine analog with demonstrated efficacy in the treatment of T-cell Lymphoblastic Leukemia and Lymphoma (T-ALL/LBL). Despite its efficacy and excellent blood-brain barrier penetration, it has a significant side effect profile which is namely concerning for neurotoxicity. Reported neurotoxicity has varied from mild peripheral neuropathy to debilitating grade 4 neurologic complications including Guillain-Barre like syndrome and myelopathy. PATIENTS AND METHODS: We conducted a single centered, retrospective case series to study patients who developed severe neurotoxicity after receiving nelarabine as part of T-ALL treatment. One hundred thirty-five patients were identified. Thirteen patients were reviewed for severe neurotoxicity (defined as ≥grade 3), and of those five patients were deemed to have neurotoxicity secondary to nelarabine exposure. RESULTS: Five patients (4%) developed severe neurotoxicity as manifested by Guillain-Barre like syndrome or myelopathy within a timeframe of eight to fifty-eight days from last nelarabine dose. Upon diagnosis, patients received formal neurologic evaluation by our neuro-oncology specialists including imaging, cerebrospinal fluid testing, and electromyography. Patients were treated with IVIG, and steroids upon diagnosis, but the majority of neuro-deficits were irreversible. CONCLUSION: Our study shows that nelarabine is generally well-tolerated, and the incidence of severe neurotoxicity is rare. Given the potential risk of severe neurotoxicity, we propose capped dose of nelarabine 1000 mg/day, neurological assessment before subsequent dosing, and avoidance of simultaneous IT therapy during nelarabine administration.
ABSTRACT
BACKGROUND: This pilot study analyzed correlations between tongue electrical impedance myography (EIM), standard tongue electromyography (EMG), and tongue functional measures in N = 4 long-term oropharyngeal cancer (OPC) survivors. METHODS: Patients were screened for a supportive care trial (NCT04151082). Hypoglossal nerve function was evaluated with genioglossus needle EMG, functional measures with the Iowa oral performance instrument (IOPI), and multi-frequency tissue composition with tongue EIM. RESULTS: Tongue EIM conductivity was higher for patients with EMG-confirmed cranial nerve XII neuropathy than those without (p = 0.005) and in patients with mild versus normal EMG reinnervation ratings (16 kHz EIM: p = 0.051). Tongue EIM correlated with IOPI strength measurements (e.g., anterior maximum isometric lingual strength: r2 = 0.62, p = 0.020). CONCLUSIONS: Tongue EIM measures related to tongue strength and the presence of XII neuropathy. Noninvasive tongue EIM may be a convenient adjunctive biomarker to assess tongue health in OPC survivors.
Subject(s)
Hypoglossal Nerve Diseases , Oropharyngeal Neoplasms , Humans , Electric Impedance , Muscle, Skeletal , Myography , Oropharyngeal Neoplasms/therapy , Outcome Assessment, Health Care , Pilot Projects , Survivors , TongueABSTRACT
Background: Guidelines by the myasthenia gravis (MG) Foundation of America suggest patients aged 18 to 50 years with non-thymomatous myasthenia gravis (NTMG) benefit from thymectomy. Our objective was to investigate utilization of thymectomy in NTMG patients outside the confines of a clinical trial. Methods: From the Optum de-identified Clinformatics Data Mart Claims Database (2007 to 2021), we identified patients diagnosed with MG between 18-50 years old. We then selected patients who received a thymectomy within 12 months of MG diagnosis. Outcomes included use of steroids, non-steroidal immunosuppressive agents (NSIS), and rescue therapy (plasmapheresis or intravenous immunoglobulin), as well as NTMG-related emergency department (ED) visits and hospital admissions. These outcomes were compared in the 6-months before and after thymectomy. Results: A total of 1,298 patients met our inclusion criteria, of whom 45 (3.47%) received a thymectomy, performed via minimally invasive surgery in 53.3% of cases (n=24). In comparing the pre- to post-operative period, we noted that steroid use increased (53.33% to 66.67%, P=0.034), NSIS use remained stable, and use of rescue therapy decreased (44.44% to 24.44%, P=0.007). Costs associated with steroid and NSIS use remained stable. However, the mean costs of rescue therapy decreased (from $13,243.98 to $8,486.26, P=0.035). Hospital admissions and ED visits related to NTMG remained stable. There were 2 readmissions within 90 days (4.44%) associated with thymectomy. Conclusions: Patients with NTMG undergoing thymectomy experienced less need for rescue therapy following resection, albeit with increased rates of steroid prescriptions. Thymectomy is infrequently performed in this patient population despite acceptable postsurgical outcomes.
ABSTRACT
INTRODUCTION: Late dysphagia that develops or persists years after head and neck cancer (HNC) is a disabling survivorship issue. Fibrosis is thought to stiffen connective tissues and compress peripheral nerve tracts, thereby contributing to diminished strength, flexibility, and in some cases denervation of swallowing muscles. Manual therapy (MT) is used in cancer survivors for pain and other indications, but it is unknown if increasing blood flow, flexibility and cervical range of motion (CROM) in the head and neck may improve late dysphagia. METHODS AND ANALYSIS: Manual Therapy for Fibrosis-Related Late Effect Dysphagia (MANTLE) is a National Cancer Institute-funded prospective single-arm pilot trial evaluating the feasibility, safety and therapeutic potential of MT in patients with late dysphagia after radiotherapy (RT) for HNC. Disease-free survivors ≥2 years after curative-intent RT for HNC with at least moderate dysphagia and grade ≥2 Common Terminology Criteria for Adverse Events version 4.0 fibrosis are eligible. The target sample size is 24 participants who begin the MANTLE programme. MANTLE is delivered in 10 MT sessions over 6 weeks with an accompanying home exercise programme (HEP). Patients then transition to a 6-week post-washout period during which they complete the HEP and then return for a final post-washout evaluation. Feasibility (primary endpoint) and safety will be examined. Serial assessments include CROM, modified barium swallow studies, quantitative MRI, electromyography (optional) and patient-reported outcomes as secondary, tertiary and exploratory endpoints. ETHICS AND DISSEMINATION: The research protocol and informed consent document was approved by the Institutional Review Board at the University of Texas MD Anderson Cancer Center. Findings will be disseminated through peer-reviewed publication that will be made publicly available on PubMed Central on acceptance for publication, in compliance with NIH public access policy. TRIAL REGISTRATION NUMBER: NCT03612531.
Subject(s)
Deglutition Disorders , Head and Neck Neoplasms , Musculoskeletal Manipulations , Deglutition Disorders/etiology , Deglutition Disorders/therapy , Fibrosis , Head and Neck Neoplasms/complications , Head and Neck Neoplasms/radiotherapy , Humans , Prospective Studies , SurvivorsABSTRACT
Expanding the US Food and Drug Administration-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.
Subject(s)
Drug-Related Side Effects and Adverse Reactions/diagnosis , Immune Checkpoint Inhibitors/adverse effects , Immunotherapy/adverse effects , Nervous System Diseases/diagnosis , Practice Guidelines as Topic , Consensus , Humans , Nervous System Diseases/chemically induced , Nervous System Diseases/immunology , Neurologists/statistics & numerical data , Oncologists/statistics & numerical data , Patient Care Team/organization & administration , Patient Care Team/statistics & numerical dataABSTRACT
BACKGROUND: Myasthenia gravis (MG) is a rare but life-threatening adverse event of immune checkpoint inhibitors (ICI). Given the limited evidence, data from a large cohort of patients is needed to aid in recognition and management of this fatal complication. METHODS: We reviewed our institutional databases to identify patients who had cancer and MG in the setting of ICI. We systematically reviewed the literature through August 2018 to identify all similar reported patients. We collected data on clinical and diagnostic features, management, and outcomes of these cases. RESULTS: Sixty-five patients were identified. Median age was 73 years; 42 (65%) were males, 31 (48%) had metastatic melanoma, and 13 (20%) had a preexisting MG before ICI initiation. Most patients received anti-PD-1 (82%). Sixty-three patients (97%) developed ICI-related MG (new onset or disease flare) after a median of 4 weeks (1 to 16 weeks) of ICI initiation. Twenty-four patients (37%) experienced concurrent myositis, and respiratory failure occurred in 29 (45%). ICI was discontinued in 61 patients (97%). Death was reported in 24 patients (38%); 15 (23%) due to MG complication. A better outcome was observed in patients who received intravenous immunoglobulin (IVIG) or plasmapheresis (PLEX) as first-line therapy than in those who received steroids alone (95% vs 63% improvement of MG symptoms, p = 0.011). CONCLUSIONS: MG is a life-threatening adverse event of acute onset and rapid progression after ICI initiation. Early use of IVIG or PLEX, regardless of initial symptoms severity, may lead to better outcomes than steroids alone. Our data suggest the need to reassess the current recommendations for management of ICI-related MG until prospective longitudinal studies are conducted to establish the ideal management approach for these patients.
Subject(s)
Antineoplastic Agents, Immunological/adverse effects , Myasthenia Gravis/etiology , Neoplasms/complications , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Immunological/therapeutic use , Biomarkers , Disease Progression , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Molecular Targeted Therapy/adverse effects , Myasthenia Gravis/diagnosis , Myasthenia Gravis/epidemiology , Neoplasms/diagnosis , Neoplasms/drug therapy , Symptom AssessmentABSTRACT
BACKGROUND: Many surgeons experience work-related pain and musculoskeletal symptoms; however, comprehensive reporting of surgeon ailments is lacking in the literature. We sought to evaluate surgeons' work-related symptoms, possible causes of these symptoms, and to report outcomes associated with those symptoms. MATERIALS AND METHODS: Five major medical indices were queried for articles published between 1980 and 2014. Included articles evaluated musculoskeletal symptoms and ergonomic outcomes in surgeons. A meta-analysis using a fixed-effect model was used to report pooled results. RESULTS: Forty articles with 5152 surveyed surgeons were included. Sixty-eight percent of surgeons surveyed reported generalized pain. Site-specific pain included pain in the back (50%), neck (48%), and arm or shoulder (43%). Fatigue was reported by 71% of surgeons, numbness by 37%, and stiffness by 45%. Compared with surgeons performing open surgery, surgeons performing minimally invasive surgery (MIS) were significantly more likely to experience pain in the neck (OR 2.77 [95% CI 1.30-5.93]), arm or shoulder (OR 4.59 [2.19-9.61]), hands (OR 2.99 [1.33-6.71], and legs (OR 12.34 [5.43-28.06]) and experience higher odds of fatigue (8.09 [5.60-11.70]) and numbness (6.82 [1.75-26.65]). Operating exacerbated pain in 61% of surgeons, but only 29% sought treatment for their symptoms. We found no direct association between muscles strained and symptoms. CONCLUSIONS: Most surgeons report work-related symptoms but are unlikely to seek medical attention. MIS surgeons are significantly more likely to experience musculoskeletal symptoms than surgeons performing open surgery. Symptoms experienced do not necessarily correlate with strain.
ABSTRACT
Peripheral nervous system damage from hematologic malignancies is related to neoplastic cells infiltration of peripheral nerves or to monoclonal antibody production cross-reacting with peripheral nerves' antigens. Neurolymphomatosis (NL), a rare manifestation of hematologic malignancies, occurs when malignant cells invade the peripheral nerves leading to various manifestations. Here, we report a case of NL with 2 hematologic malignancies in a 79-year-old woman presenting with lower extremity pain/weakness. Investigation revealed anemia, IgM kappa monoclonal gammopathy, and elevated anti-MAG titer. Electrodiagnostic studies were consistent with mononeuropathy multiplex while imaging suggested malignancy in her ovaries and right S1 nerve root. Bone marrow and ovarian biopsies revealed chronic myelomonocytic leukemia, Waldenstrom macroglobulinemia, and diffuse large B-cell lymphoma. She received standard chemotherapy resulting in radiographic resolution of disease and symptomatic relief. NL can precede the diagnosis of hematologic malignancy but its symptoms are not easily identifiable, whereas management depends on the treatment of the underlying tumor.
Subject(s)
Hematologic Neoplasms/diagnostic imaging , Hematologic Neoplasms/physiopathology , Marek Disease/physiopathology , Aged , Animals , Female , Fluorodeoxyglucose F18 , Humans , Magnetic Resonance Imaging , Marek Disease/diagnostic imaging , Peripheral Nerves/diagnostic imaging , Peripheral Nerves/pathology , Positron-Emission TomographyABSTRACT
Intrathecal chemotherapy with methotrexate, a folate antagonist, is widely used to treat central nervous system malignancies. The mechanisms underlying methotrexate-induced neurotoxicity are unclear but may be related to increased homocysteine levels. Intrathecal methotrexate-induced myelopathy mimicking subacute combined degeneration, with normal B12 levels, has been documented. We examined treatment and magnetic resonance imaging (MRI) characteristics of 13 patients with leukemia who received intrathecal methotrexate and developed urinary and bowel incontinence, ascending motor weakness, and sensory loss with dorsal column hyperintensity on MRI between 2000 and 2016. Cerebrospinal fluid evaluation was negative for leukemia in all patients and positive for elevated protein in 12 patients. Seven of eight patients with available data had reduced serum folate, increased serum homocysteine, or both, implicating methotrexate as the cause of neurotoxicity. Autopsy of one patient revealed loss of myelinated axons in the posterior columns. These findings suggest that methotrexate neurotoxicity may be mediated by folate antagonism. Awareness and a high index of suspicion of these characteristic clinical and radiographic features in patients who develop myelopathy after intrathecal methotrexate may help to avoid additional neurotoxic therapy in such patients.
Subject(s)
Antimetabolites, Antineoplastic/adverse effects , Leukemia/drug therapy , Methotrexate/adverse effects , Spinal Cord Diseases/chemically induced , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/therapeutic use , Diagnosis, Differential , Electronic Health Records , Female , Folic Acid/blood , Homocysteine/blood , Humans , Injections, Spinal , Leukemia/blood , Magnetic Resonance Imaging , Male , Methotrexate/administration & dosage , Methotrexate/therapeutic use , Spinal Cord Diseases/cerebrospinal fluid , Spinal Cord Diseases/diagnostic imaging , Subacute Combined Degeneration/diagnosisABSTRACT
Methotrexate and cytarabine arabinoside are frequently administered intrathecally in the prophylaxis and treatment of patients with hematological malignancies. Myelopathy as a complication of intrathecal (IT) chemotherapy is rare in adults, with most of the cases described in the literature occurring in the pediatric population. Between January 2010 and March 2014, 587 newly diagnosed B cell acute lymphoblastic leukemia and 24 chronic myeloid leukemia lymphoid blast phase patients were seen at The University of Texas MD Anderson Cancer Center. This case series discusses seven adult cases deemed to have IT chemotherapy-induced myelopathy between 2010 and 2014 at MD Anderson Cancer Center. Five out of the seven patients had T2 abnormalities involving the dorsal columns of the spinal cord. An elevated myelin basic protein level was noted in the two patients in whom it was checked. The wide range of dosage and timing with respect to IT chemotherapy administration suggests an idiosyncratic reaction or individual threshold to the development of myelopathy. By describing the largest case series of myelopathy in adults, we aim to raise awareness about this rare albeit devastating complication. Based on the seven cases described we would recommend-MRI of the spine with T2-weighted imaging in the sagittal and axial planes in leukemia patients with unexplained myelopathy and consideration to delay IT chemotherapy until after an extensive work-up to rule out CNS leukemia. Though more data are needed on the use of folate metabolites, preliminary results have shown some promise in the treatment of methotrexate-induced myelopathy and may be a potential consideration for future patients suspected to have chemotherapy induced myelopathy.
Subject(s)
Antimetabolites, Antineoplastic/adverse effects , Cytarabine/adverse effects , Methotrexate/adverse effects , Spinal Cord Diseases/chemically induced , Adolescent , Adult , Aged , Antimetabolites, Antineoplastic/administration & dosage , Cytarabine/administration & dosage , Female , Humans , Injections, Spinal/adverse effects , Leukemia, B-Cell/complications , Leukemia, B-Cell/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Magnetic Resonance Imaging/methods , Male , Methotrexate/administration & dosage , Middle Aged , Myelin Basic Protein/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Spinal Cord/drug effects , Spinal Cord/pathology , Spinal Cord Diseases/pathology , Spinal Cord Diseases/physiopathologyABSTRACT
BACKGROUND: Neurolymphomatosis (NL) is a rare clinical entity characterized by infiltration of malignant lymphocytes into the peripheral nervous system. We analyzed the clinicoradiological features, treatments, and outcomes in NL patients. METHODS: We identified six patients with NL seen at The University of Texas MD Anderson Cancer Center from 01/2010 to 10/2012. We extracted clinical presentations, imagings, CSF cytology, and electrodiagnostic studies from medical records. One patient had a nerve biopsy. We defined therapy response as clinical improvement of neurological deficits. FINDINGS: The mean age at onset was 57.1 years. Most were predominantly men with non-Hodgkin lymphoma. Positron emission tomography (PET) was positive in five patients. Nerve conduction demonstrated mononeuritis multiplex, plexopathy, demyelination, and axonal polyradiculoneuropathy, whereas electromyography was nonspecific. All patients received systemic chemotherapy, four intrathecal chemotherapy, and three intravenous immunoglobulin, plasma exchange or both. One patient who received intravenous immunoglobulin showed mild neurological improvement. Two patients responded, and the median overall survival was 15 months. CONCLUSIONS: NL is an increasingly recognized complication of NHL and leukemia. A high clinical suspicion is necessary for correct diagnosis. In the present series, patients with leukemia had mononeuritis multiplex, whereas those with lymphoma had plexopathy. Electrodiagnosis and PET scans were useful diagnostic tools. No factors correlated with poorer prognosis. International collaborative studies will help to better determine the risk factors of NL, response to treatment and outcomes.
Subject(s)
Marek Disease/diagnosis , Marek Disease/therapy , Treatment Outcome , Adult , Aged , Animals , Birds , Brachial Plexus/pathology , Female , Fluorodeoxyglucose F18 , Humans , Immunoglobulins, Intravenous/therapeutic use , Magnetic Resonance Imaging , Male , Marek Disease/complications , Marek Disease/diagnostic imaging , Middle Aged , Plasma Exchange , Positron-Emission TomographyABSTRACT
BACKGROUND: Parvovirus B19 is a single-stranded DNA virus belonging to the family Parvoviridae, genus Erythrovirus. PVB19 infection is most common in the pediatric population, manifesting as erythema infectiosum. In patients with hemoglobinopathy, PVB19 infection is known to cause aplastic anemia. PVB19 infection rarely affects the nervous system - reported manifestations include seizures, encephalitis and meningoencephalitis. Less common presentations include stroke, cerebellar ataxia, optic neuritis, brachial plexitis, Guillain-Barré syndrome and carpal tunnel syndrome. METHODS: Review the different central nervous system (CNS) manifestations and treatment strategies in all reported cases of adult CNS PVB19 infection. RESULTS: Cerebellar ataxia is a very rare manifestation of PVB19 CNS infection. Our patient had refractory chronic lymphocytic leukemia and PVB19 in bone marrow and serum; he presented with 6-week history of progressive pan-cerebellar ataxia. CSF was acellular but PVB19 was present on PCR test. Early treatment with intravenous immunoglobulin (IVIG) led to improvement in the patient's neurological deficits. CONCLUSIONS: PVB19 CNS infection should be in the differential as a cause of cerebellar ataxia in immunocompromised patients. Recognition is critical to early institution of appropriate therapy. Our patient showed considerable improvement in ataxia after IVIG therapy.